Uncoupling protein-2 (UCP2) is a mitochondrial protein that negatively regulates ATP production. In pancreatic ?-cells, UCP2 affects glucose-stimulated insulin secretion. UCP2 is also expressed in the brain. In glucose-excited neurons (specifically, POMC neurons in the arcuate nucleus and MCH neurons in the lateral hypothalamus), UCP2 is active and it negatively regulates glucose-stimulated activation. This has important consequences for regulation of whole body glucose homoeostasis. The focus of the Parent R37 grant is to study the role of KATP channels and UCP2 in glucose-excited neurons (specifically in POMC neurons, MCH neurons and SF1 neurons). In this Competitive Revision, we propose to study the role of UCP2 in AgRP neurons in regulating feeding behavior. Our studies on glucose-excited neurons (mentioned above) have demonstrated that UCP2 activity within neurons can have important effects on physiologic processes. Since UCP2 is also expressed by AgRP neurons, we hypothesize that UCP2 within AgRP neurons modulates feeding behavior (a process strongly controlled by AgRP neurons). In preliminary studies, we have found that global UCP2 gene knockout mice have the following abnormalities: 1) increased refeeding following a fast, 2) increased hyperphagic response to ghrelin, and 3) increased NPY mRNA and AgRP mRNA levels in the hypothalamus. Based upon these findings, we hypothesize that UCP2 within AgRP neurons inhibits feeding behavior, and that it does this by modulating ghrelin-mediated activation of AgRP neurons. To test this hypothesis, we put forth the following Aims (to be conducted over a 2 year period): Aim 1: To determine if UCP2 within AgRP neurons regulates feeding and responsiveness to ghrelin. To test our hypothesis, we will cross AgRP-ires-Cre mice with lox-UCP2 mice. We will then assess feeding following an overnight fast and also the hyperphagic response to ghrelin. Aim 2: To determine if UCP2 within AgRP neurons regulates the firing rate of AgRP neurons, and secondarily, the frequency of GABAergic IPSCs into POMC neurons (a functionally important downstream target of AgRP neurons). PUBLIC HEALTH RELEVANCE: Abnormalities in feeding behavior cause disease: obesity and anorexia nervosa. This application focuses on the role of mitochondria within hypothalamic neurons in regulating feeding behavior. Specifically, we hypothesize that uncoupling protein-2 within neurons plays an important role in regulating appetite.